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PubMed2006

Methemoglobinemia following transesophageal echocardiography: a case report and review.

Benzocaine (ethyl aminobenzoate) is a topical anesthetic widely used for oropharyngeal anesthesia prior to transesophageal echocardiography (TEE). Topical anesthetics have been reported to cause methemoglobinemia, but this adverse event is extremely rare and has not been listed as one of the possible complications of TEE. However, recently the number of published case reports of TEE-associated methemoglobinemia has increased. Since its first description in 1950, 65 cases of methemoglobinemia have been reported including a recent report of five cases from a single center. Physicians who are not familiar with the association of TEE with benzocaine-induced methemoglobinemia may not recognize the idiosyncratic and often nonspecific characteristic of this condition. Recognition is critical, however, since left untreated methemoglobinemia can lead to cardiopulmonary compromise, neurological sequelae, and even death. The current report documents an additional case of TEE-associated methemoglobinemia from a high-volume (8000 cases /year including 400-450 TEE/year) echo lab. A review of the literature suggests that this complication may be more prevalent, than generally appreciated. This case report emphasizes the importance of appropriate dose, recognition, and the treatment of this entity to cardiologists performing TEE.

Aged↗

PubMed1982

Acquired methemoglobinemia and hemolytic anemia after usual doses of phenazopyridine.

Two patients developed symptomatic methemoglobinemia and hemolytic anemia after treatment with phenazopyridine. Methemoglobinemia appears to be a rare occurrence after commonly used doses of phenazopyridine; phenazopyridine-associated hemolytic anemia has been reported both after overdose and after usual doses. The presentation of methemoglobinemia in the first patient and the response to treatment with methylene blue in the second patient were unusual, suggesting that the patients had a red cell defect or were exposed to other oxidizing substances. One of the major metabolites of phenazopyridine is aniline, a known cause of methemoglobinemia. Aniline-induced methemoglobinemia is less responsive to treatment with methylene blue than nitrate- or nitrite-induced methemoglobinemia. This may explain, in part, the poor response to methylene blue by one of our patients.

Aged↗

PubMed2004

[Methemoglobinemia in children as a differential diagnosis of cyanosis].

Methemoglobinemia is characterized by cyanosis with various degrees of severity. Symptoms range from asymptomatic to unconsciousness and death. Although cyanosis caused by methemoglobinemia is well-documented in the literature, it is rare and the consequences can be fatal. The cause of methemoglobinemia can be environmental, acquired, congenital or a combination of the above. Among the potential sources for methemoglobinemia are local anaesthetics that are in common use in hospitals and clinics, some of which can be purchased without prescription. Although these drugs are considered to be safe, they can still induce methemoglobinemia and can be life-threatening. In this review we describe patients admitted to the Pediatric Intensive Care Unit during the year 2000 suffering from cyanosis and diagnosed as having methemoglobinemia.

Child↗

PubMed1996

Protracted methemoglobinemia after phenazopyridine overdose in an infant.

Acquired methemoglobinemia may be produced by the ingestion or absorption of certain chemicals and xenobiotics. A case of methemoglobinemia in an 8.5-month old infant who ingested approximately 227 mg/kg of phenazopyridine is presented. Although this adverse event is often reversed with a single dose of methylene blue, this patient required three doses of methylene blue (1 mg/kg) over a 25-hour period. It is suggested that the need for repeated doses of methylene blue in this case was not only related to the large dose of phenazopyridine, but also its metabolites (i.e., aniline), which have the potential to produce methemoglobinemia. This case illustrates the need for close observation and serial monitoring of methemoglobin levels in patients who are at increased risk for the development of protracted methemoglobinemia. Integration of knowledge of developmental pharmacology, drug metabolism, and pharmacodynamic properties are critical determinants in the evaluation and treatment of patients with drug-induced methemoglobinemia.

Adolescent↗

PubMed1994

Evaluation of the methemoglobinemia associated with sulofenur.

A new class of antineoplastic agents, the diarylsulfonylureas entered clinical trials with the testing of Sulofenur (LY186641). Phase I trials and preclinical studies showed the dose limiting toxicity to be methemoglobinemia. We studied the incidence of methemoglobinemia, sulfhemoglobinemia and cytochrome b5 reductase deficiency in nine consecutive patients enrolled in a phase II trials using Sulofenur. The specific Malloy method as well as clinically standard co-oximeter measurements were used to determine methemoglobin levels and marked discrepancies were noted. One patient with symptomatic methemoglobinemia had enzyme levels and family history consistent with a heterozygous state for a cytochrome b5 reductase deficiency. We conclude that the clinical incidence of methemoglobinemia will be overestimated by co-oximeter measurements but that Sulofenur does produce clinically significant methemoglobinemia in cytochrome b5 reductase deficient patients.

Antineoplastic Agents↗

PubMed1991

Species differences in susceptibility to 1,3-dinitrobenzene-induced testicular toxicity and methemoglobinemia.

The testicular toxicity and methemoglobinemia induced by 1,3-dinitrobenzene (1,3-DNB) was compared in two species, the Sprague-Dawley rat and the golden Syrian hamster. A marked difference in susceptibility to both endpoints of toxicity was observed. The hamster showed no testicular lesions at dose levels up to 50 mg/kg whereas, as previously reported by others, damage to rat testicular tubules in later stages of spermatogenesis was readily apparent at a 25 mg/kg dose level. Similarly, administration of 1,3-DNB induced substantially less methemoglobinemia in the hamster than in the rat. For example, at the 25 mg/kg dose level peak levels of methemoglobin in the hamster were 15% compared with 80% in the rat. Mortality in the rat also occurred at lower doses than in the hamster (50 vs 100 mg/kg, respectively). In in vitro studies, the capacity of 1,3-DNB and 1,3-DNB metabolites (nitroaniline, nitroacetanilide, aminoacetanilide, diacetamidobenzene) to induce methemoglobinemia was examined in suspensions of red blood cells obtained from both species. Only 1,3-DNB caused the formation of methemoglobin and rat red blood cells were twice as sensitive as hamster red blood cells. The species difference in susceptibility to both methemoglobinemia and testicular toxicity could indicate differences in 1,3-DNB clearance and/or formation of toxic metabolites. Additional metabolic work is under way. This study demonstrates that the hamster is more resistant than the rat to the testicular lesion and methemoglobinemia induced by 1,3-DNB.

Animals↗

PubMed2005

A case with quadriparetic cerebral palsy and cyanosis: congenital methemoglobinemia.

The recessive form of congenital methemoglobinemia, caused by a defect of nicotinamide adenine dinucleotide-cytb5 reductase enzyme (cytb5r), is a rare disorder clinically presenting with cyanosis. Two different forms of recessive congenital methemoglobinemia have been described: In type I, cyanosis is the only major symptom and enzyme deficiency is restricted to erythrocytes. In type II, observed in 10-15% of all patients, enzyme deficiency occurs in the entire body and cyanosis is associated with severe, progressive neurologic impairment. This report presents a 10-year-old female with recessive congenital methemoglobinemia type II. She was admitted with quadriparetic cerebral palsy, mental retardation, convulsions, swallowing difficulty, and cyanosis. Etiology of cyanosis was not clarified exactly but was readily but erroneously attributed to uncontrolled, repetitive convulsions and aspiration of excessive oral secretions. Her methemoglobin level was measured as 51%, and a diagnosis of congenital methemoglobinemia was established. Oral ascorbic acid 500 mg/day was initiated. She responded well to therapy. Interestingly, neurologic deficits improved after ascorbic acid treatment. In conclusion, cyanosis and repetitive convulsions associated with neurologic deficits may be explained by congenital methemoglobinemia, a potentially treatable condition.

Cerebral Palsy↗

PubMed2003

The structure of the S127P mutant of cytochrome b5 reductase that causes methemoglobinemia shows the AMP moiety of the flavin occupying the substrate binding site.

Methemoglobinemia, the first hereditary disease to be identified that involved an enzyme deficiency, has been ascribed to mutations in the enzyme cytochrome b(5) reductase. A variety of defects in either the erythrocytic or microsomal forms of the enzyme have been identified that give rise to the type I or type II variant of the disease, respectively. The positions of the methemoglobinemia-causing mutations are scattered throughout the protein sequence, but the majority of the nontruncated mutants that produce type II symptoms occur close to the flavin adenine dinucleotide (FAD) cofactor binding site. While X-ray structures have been determined for the soluble, flavin-containing diaphorase domains of the rat and pig enzymes, no X-ray or NMR structure has been described for the human enzyme or any of the methemoglobinemia variants. S127P, a mutant that causes type II methemoglobinemia, was the first to be positively identified and have its spectroscopic and kinetic properties characterized that revealed altered nicotinamide adenine dinucleotide hydride (NADH) substrate binding behavior. To understand these changes at a structural level, we have determined the structure of the S127P mutant of rat cytochrome b(5) reductase to 1.8 A resolution, providing the first structural snapshot of a cytochrome b(5) reductase mutant that causes methemoglobinemia. The high-resolution structure revealed that the adenosine diphosphate (ADP) moiety of the FAD prosthetic group is displaced into the corresponding ADP binding site of the physiological substrate, NADH, thus acting as a substrate inhibitor which is consistent with both the spectroscopic and kinetic data.

Adenosine Monophosphate↗

PubMed2006

Methemoglobinemia caused by the ingestion of courgette soup given in order to resolve constipation in two formula-fed infants.

Methemoglobinemia is not a rare condition arising from the exposure to hemoglobin-oxidizing agents such as nitrates-nitrites present in well water or vegetables. Infants < 3 months of age are more susceptible than adults because of lower amounts of a key enzyme, NADH-cytochrome b5 reductase, which converts methemoglobin back to hemoglobin. We report 2 infants, aged respectively 2 and 1 months, suffering from methemoglobinemia, fed with a formula that was reconstituted with a high concentration of courgette soup to resolve constipation. They developed a severe cyanosis with methemoglobinemia (respectively 30.4 and 27%) and were hospitalized and treated with methylene blue at 1%. After 12 h the syndrome was completely resolved. Home-prepared infant foods containing vegetables are potential causes of methemoglobinemia. It is important not to feed infants with vegetables having a high nitrate content (e.g., courgette, spinach, beets and green beans) to resolve constipation since, particularly in the first months of life, they may cause severe methemoglobinemia.

Constipation↗

PubMed1996

Methemoglobinemia induced by an over-the-counter medication.

OBJECTIVE: To report a case of methemoglobinemia induced by benzocaine and resorcinol (Vagisil) cream, an over-the-counter medication that was used to treat diaper rash in a neonate. CASE REPORT: A 6-day-old, 3350-g white boy was found to be cyanotic with blue mucous membranes on presentation. He had a diaper rash that was red and irritated, which his mother had treated with Vagisil cream. Methemoglobinemia secondary to absorption of benzocaine and resorcinol (1,3-benzenediol) from the Vagisil was diagnosed, with a methemoglobin level of 35% on admission (normal 0.4-1.5). Intravenous methylene blue 3 mg (1 mg/kg) was given; the neonate's skin color returned to normal 45 minutes after the dose. DISCUSSION: Methemoglobinemia is a condition in which hemoglobin is oxidized to the ferric form. Oxidized hemoglobin, methemoglobin, is incapable of reversibly binding oxygen at the physiologic partial oxygen pressure. Main causes of methemoglobin formation are exposure to certain oxidizing agents and drugs, deficiency of one of the enzymes necessary for reduction of methemoglobin to hemoglobin, or the presence of an abnormal hemoglobin resistant to reduction. Clinical manifestations of methemoglobinemia include diffuse slate-gray cyanosis with low oxygen saturation in the absence of respiratory distress. A single intravenous dose of methylene blue 1-2 mg/kg is the treatment of choice. CONCLUSIONS: Newborn infants are at increased risk for methemoglobinemia due to diminished enzyme systems required to reduce ferrihemoglobin to ferrohemoglobin, as well as because fetal hemoglobin is more easily oxidized than is adult hemoglobin. It is important to recognize possible drug reactions and educate parents on the potential risks of treatment with over-the-counter medications, especially in neonates.

Adult↗

PubMed1998

Dapsone-induced methemoglobinemia.

OBJECTIVE: To report a case of methemoglobinemia in a patient receiving dapsone for prophylaxis of Pneumocystis carinii pneumonia (PCP). CASE SUMMARY: A 69-year-old white woman was hospitalized to rule out sepsis. Two years prior to this admission, the patient received an orthotopic liver transplant after which she required hemodialysis three times weekly. Because of intolerance to trimethoprim/ sulfamethoxazole and aerosolized pentamidine, she was prescribed dapsone therapy on hospital day 13, that was continued for 11 days. On hospital day 45 the patient received a cadaveric kidney transplant, and dialysis treatments were scheduled only as needed. One week after the transplant, dapsone therapy was resumed. Nine days into this course of dapsone, the patient developed dyspnea and oxygen desaturation of unknown etiology. The patient was evaluated for and diagnosed with methemoglobinemia. She received two doses of intravenous methylene blue and one dose of oral activated charcoal due to fluctuating methemoglobin concentrations. DISCUSSION: The elimination of dapsone is not completely understood. Several case reports of dapsone-induced methemoglobinemia are present in the literature. Most have occurred in patients who have accidentally or deliberately overdosed. Cases of methemoglobinemia in patients receiving therapeutic doses of dapsone are discussed. CONCLUSIONS: The growing numbers of immunosuppressed patients due to transplantation of HIV may result in increased dapsone use for the prevention of PCP. Clinicians should be aware of the adverse effects associated with dapsone therapy, and patients with dyspnea and hypoxemia of unclear etiology should be evaluated for methemoglobinemia.

Aged↗

PubMed1999

When patients become cyanotic: acquired methemoglobinemia.

BACKGROUND: The authors conducted literature review to create a heightened awareness of the potential for developing toxic methemoglobinemia from local anesthetics. Methemoglobin normally is present in the blood at levels less than 1 percent. Levels may become toxic as hemoglobin is oxidized to methemoglobin after local anesthetics such as benzocaine and prilocaine are administered. TYPES OF STUDIES REVIEWED: The authors searched the medical and pharmaceutical industry literature. They found and reviewed case studies of incidences of methemoglobinemia that resulted from local anesthetic overdoses. RESULTS: Cases of local anesthetic-induced methemoglobinemia in dental practice are under-recognized and rare. Reported cases of prilocaine-induced methemoglobinemia have resulted in recent changes in some prilocaine literature. These changes include maximum recommended doses for patients of various weights. CLINICAL IMPLICATIONS: Dentists should identify patients who are at increased risk of developing methemoglobinemia before administering local anesthetics. They also should follow new recommended dosing guidelines for prilocaine and be aware of symptoms of this adverse reaction.

Anesthesia, Dental↗

PubMed2006

Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: a case report and review of the literature.

Severe methemoglobinemia resulting from the use of topical benzocaine has been reported in adults as a rare complication. Here we report a case of severe acquired methemoglobinemia resulting from topical use of benzocaine spray during diagnostic upper gastrointestinal endoscopy in a 3-year-old boy with repeated episodes of hematemesis 3 weeks posttonsillectomy. He developed marked cyanosis and became increasingly agitated immediately after completion of his unremarkable endoscopic procedure, which was performed under intravenous sedation. He did not respond to maximum supplemental oxygen and had increased respiratory effort. His pulse oximetry dropped to 85%, but simultaneous arterial blood-gas analysis showed marked hypoxemia (Po2 = 29%) and severe methemoglobinemia (methemoglobin = 39%). His cyanosis and altered mental status promptly resolved after intravenous administration of methylene blue. In patients with methemoglobinemia, pulse oximetry tends to overestimate the actual oxygen saturation and is not entirely reliable. Posttonsillectomy bleeding is a rare but occasionally serious complication that could occur weeks after the surgery, although it more commonly occurs within the first few days. Physicians should remain aware of the possibility of its late onset. This case illustrates the severity of acquired methemoglobinemia that may result from even small doses of topical benzocaine and highlights the fact that prompt treatment of the disorder can be life saving. We question the rationale for routine use of topical anesthetic spray for sedated upper gastrointestinal endoscopy in children. By bringing the attention of pediatricians to this rare but serious complication, we hope that it will result in its improved recognition and possible prevention.

Administration, Topical↗

PubMed2005

Benzocaine-induced methemoglobinemia.

A case is reported in which a patient developed methemoglobinemia-induced cyanosis while under general anesthesia during surgery for multiple fascial space infections. The cause of methemoglobinemia was 20% benzocaine spray used for local anesthesia before intubation. Acutely developing methemoglobinemia is infrequently encountered in clinical practice. When confronted with cyanosis in the absence of cardiac or pulmonary disease, one must seriously consider the diagnosis of methemoglobinemia. The etiology of methemoglobinemia, the causative agents, the diagnosis, and the emergency treatment required are discussed.

Abscess↗

PubMed2000

Metoclopramide-induced methemoglobinemia in an adult.

Methemoglobinemia is a condition characterized by increased level of methemoglobin in the erythrocytes and brownish cyanosis. Acquired methemoglobinemia is diagnosed by elevated methemoglobin with normal hemoglobin electrophoresis and normal NADH cytochrome b5 reductase. We report a patient who developed lethargy, confusion, and cyanosis during post-operative period. He had arterial methemoglobin level of 40.6% and oxygen saturation of 59%. No other cause could be found for his methemoglobinemia other than metoclopramide, even though it is rarely reported to cause methemoglobinemia in adults compared to infants. He had an excellent clinical response to treatment with methylene blue with which his clinical symptoms improved and the methemoglobin level returned to normal within 24 hours. Here we discuss the clinical features, diagnosis, and treatment of acquired methemoglobinemia induced by metoclopramide.

Aged↗

PubMed2000

A Thai boy with hereditary enzymopenic methemoglobinemia type II.

Individuals with methemoglobin exceeding 1.5 g/dl have clinically obvious central cyanosis. Hereditary methemoglobinemia is due either to autosomal dominant M hemoglobins or to autosomal recessive enzymopenic methemoglobinemia. Four types of enzymopenic methemoglobinemia have been described. In addition to methemoglobinemia, individuals with type II, which is the generalized cytochrome b5 reductase deficiency, have severe and progressive neurological disabilities. Here we report a 3-year-old Thai boy with type II hereditary enzymopenic methemoglobinemia. He was born to a second-cousin couple. His central cyanosis was first observed around 10 months of age. His neurological abnormalities were seizures beginning at 1 year of age, microcephaly, and inability to hold his head up. His cardiovascular and pulmonary evaluations were unremarkable. Methemoglobin level by spectral absorption pattern was 18 per cent. A qualitative enzymatic assay confirmed the deficiency of the cytochrome b5 reductase enzyme. With this definite diagnosis, a prenatal diagnosis for the next child of this couple will be possible.

Child, Preschool↗

PubMed1987

Contribution of aniline metabolites to aniline-induced methemoglobinemia.

Methemoglobinemia after aniline and certain aniline derivatives is thought to be mediated by toxic metabolites formed during the hepatic clearance of the parent compounds. However, three aniline metabolites--phenylhydroxylamine, 2-aminophenol, and 4-aminophenol--catalyze methemoglobin formation in erythrocyte suspensions and, hence, could contribute to methemoglobin formation in vivo after aniline. To determine the relative contributions of these aniline metabolites to aniline-induced methemoglobinemia in rats, we determined time courses of methemoglobinemia in rat erythrocyte suspensions and in rats after treatment with 2- and 4-aminophenol, phenylhydroxylamine, and aniline. The relative potencies for methemoglobin production in vitro after phenylhydroxylamine, 2-aminophenol, and 4-aminophenol were about 10:5:1, based on both peak and area of the methemoglobin versus time curve. Approximate minimum concentrations for observable methemoglobin formation in vitro from these compounds were 20, 50, and 200 microM, respectively. Compared with the in vitro data, the relative potencies of the aminophenols for methemoglobinemia in rats after intraperitoneal injections were reduced with respect to phenylhydroxylamine (to 100:4:1, respectively), apparently as a result of rapid in vivo clearance of the aminophenols. Subsequent experiments, in which the time courses of the aniline metabolites were determined in blood after toxic doses of aniline, demonstrated that only phenylhydroxylamine (measured as phenylhydroxylamine + nitrosobenzene) accumulated to blood levels exceeding the minimum concentration required for methemoglobin production in vitro. In addition, blood levels of phenylhydroxylamine remained in the toxic range throughout most of the methemoglobinemic response after aniline treatment. These data are consistent with phenylhydroxylamine being the sole mediator of aniline-induced methemoglobinemia in these rats.

Aminophenols↗

PubMed1982

Enzymopenic hereditary methemoglobinemia.

The normal erythrocyte is well endowed with a system to convert useless methemoglobin to functional hemoglobin. The major mechanism for this reductive capacity resides in the soluble cytochrome b5/NADH cytochrome b5 reductase of the cytosol which presumably arise from the microsomal proteins of the endoplasmic reticulum through proteolytic cleavage of the proteins' hydrophobic tails during the maturation of nucleated erythrocyte precursors. NADH cytochrome b5 reductase is coded for by a gene on the human chromosome 22. Inheritance of a pair of abnormal alleles which specify an enzyme with decreased activity or stability occurs only rarely, but leads to enzymopenic hereditary methemoglobinemia. Type I, uncomplicated, benign methemoglobinemia is attributed to mutation in paired alleles that affect primarily the catalytic capacity, stability, or solubilization of the polar, soluble segment of the enzyme. It does not appear to affect significantly the well being or life expectancy of the homozygous subject. The cosmetic affliction or the minimal symptoms can rather easily be controlled with methylene blue, ascorbic acid, or riboflavin. The heterozygote is entirely asymptomatic, but may have an increased tendency to develop methemoglobinemia on exposure to methemoglobin-inducing drugs or chemicals. Type II, severe lethal methemoglobinemia is a generalized disorder in which the NADH cytochrome b5 reductase is apparently defective in all tissues. It is thought to result from either gene deletion or mutation in paired alleles that determine the function, stability, or attachment to the endoplasmic reticulum of the entire enzyme, both the polar and the hydrophobic segments. As in Type I, the heterozygote is asymptomatic, and the homozygote's methemoglobinemia is readily controlled. The generalized disorder including the neurologic dysfunction, however, is not amenable to treatment at this time. Prenatal diagnosis by examination of amniotic fluid cells is both feasible and useful.

Cytochrome Reductases↗